CN1122662C - Arylsulfonylamino hydroxamic acid derivatives - Google Patents
Arylsulfonylamino hydroxamic acid derivatives Download PDFInfo
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- CN1122662C CN1122662C CN96193213A CN96193213A CN1122662C CN 1122662 C CN1122662 C CN 1122662C CN 96193213 A CN96193213 A CN 96193213A CN 96193213 A CN96193213 A CN 96193213A CN 1122662 C CN1122662 C CN 1122662C
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
Abstract
A compound of formula (I), wherein n, X, R<3>, R<4> and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF.
Description
Background of invention
The present invention relates to Arenesulfonyl amino-iso hydroximic acid derivative, therefore they are inhibitor of matrix metalloproteinase or tumour necrosis factor (hereinafter also being referred to as TNF) product, and can be used for treating following disease: sacroiliitis, cancer, tissue ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other are active with matrix metalloproteinase to be that the disease, acquired immune deficiency syndrome (AIDS), sepsis, septic shock of characteristics and other relate to the disease of TNF product.
The invention still further relates to and utilize such compounds for treating to suffer from the Mammals of above-mentioned disease, particularly people's method, and the pharmaceutical composition that is used for these methods.
There are many enzymes can influence the disassociation of structural protein, and they and metalloprotease structurally associated.Substrate degradation metalloprotease such as gelatinase, stromelysin and collagenase, relevant with periplast's degraded (for example: collagen withers), and involve many unusual knot a kind of thick silk tissue and metabolic pathological conditions of basement membrane matrix of relating to, as sacroiliitis (for example osteoarthritis and rheumatoid arthritis), tissue ulcer's (for example keratohelcosis, epidermis ulcer and stomach ulcer), unusual wound healing, periodontal disease, osteopathia (for example Paget disease and osteoporosis), metastases or intrusion, and the HIV infection (
Leukemia and biology magazine,
52(2): 244-248,1992).
That tumour necrosis factor is considered to is relevant with many infectivity and autoimmune disorder (W.Friers,
Europe biological chemistry association associating wall bulletin, 1991,
285, 199).
In addition, studies show that TNF be observed inflammatory reaction in sepsis and septic shock main transmission medium (people such as C.E.Spooner,
Clinical immunology and immunopathology, 1992,
62S11).
European patent publication 606046 is mentioned the sulphonyl oxygen hydroxamic acid compound (sulfoxyhydroxamic compounds) that has matrix metalloproteinase inhibitory activity.With the substituent R on the methylene radical that the nitrogen-atoms of sulfonamido among the formula I links to each other, its structure is different from corresponding-C (O) X base in the following formula I compound.
Summary of the invention
The present invention relates to formula I compound or its pharmacy acceptable salt,
Wherein:
N is 1-6;
X is hydroxyl, (C1-C
6) alkoxyl or NR1R
2, R wherein1And R2Be hydrogen, (C independently of one another1-C
6) alkyl, piperidyl, (C1-C
6) Alkylpiperidine base, (C6-C
10) Arylpiperidine base, (C5-C
9) heteroaryl piperidine base, (C6-C
10) aryl (C1-C
6) Alkylpiperidine base, (C5-C
9) heteroaryl (C1-C
6) Alkylpiperidine base, (C1-C
6) acyl group piperidyl, (C6
-C
10) aryl, (C5-C
9) heteroaryl, (C6-C
10) aryl (C1-C
6) alkyl, (C5
-C
9) heteroaryl (C1-C
6) alkyl, (C6-C
10) aryl (C6-C
10) aryl, (C6
-C
10) aryl (C6-C
10) aryl (C1-C
6) alkyl, (C3-C
6) cycloalkyl, (C3
-C
6) cycloalkyl (C1-C
6) alkyl, R5(C
2-C
6) alkyl, (C1-C
5) alkyl (CHR5)
(C
1-C
6) alkyl, wherein R5For hydroxyl, (C1-C
6) acyloxy, (C1-C
6) alkoxyl, piperazine subbase, (C1-C
6) acyl group is amino, (C1-C
6) alkyl sulfenyl, (C6-C
10) arylthio, (C1-C
6) alkyl sulfinyl, (C6-C
10) aryl sulfinyl, (C1-C
6) alkylsulfonyloxy (sulfoxyl), (C6-C
10) aryl-sulfonyl oxygen, amino, (C1-C
6) alkyl amino, ((C1-C
6) alkyl)2Amino, (C1-C
6) acyl group piperazine subbase, (C1
-C
6) alkyl piperazine sub-base, (C6-C
10) aryl (C1-C
6) alkyl piperazine sub-base, (C5
-C
9) heteroaryl (C1-C
6) alkyl piperazine sub-base, morpholino, thiomorpholine generation, piperidino or pyrrolidino (pyrrolidino), R6(C
1-C
6) alkyl, (C1-C
5) alkyl (CHR6)
(C
1-C
6) alkyl, wherein R6Piperidyl, (C1-C
6) Alkylpiperidine base, (C6-C
10) Arylpiperidine base, (C6-C
10) aryl (C1-C
6) Alkylpiperidine base, (C5-C
9) heteroaryl piperidine base or (C5-C
9) heteroaryl (C1-C
6) the Alkylpiperidine base; And CH (R7)COR
8, R wherein7Hydrogen, (C1-C
6) alkyl, (C6-C
10) aryl (C1-C
6) alkyl, (C5
-C
9) heteroaryl (C1-C
6) alkyl, (C1-C
6) alkylthio (C1-C
6) alkyl, (C6
-C
10) aryl sulfo-(C1-C
6) alkyl, (C1-C
6) alkyl sulfinyl (C1-C
6) alkyl, (C6-C
10) aryl sulfinyl (C1-C
6) alkyl, (C1-C
6) alkyl sulfonyl (C1
-C
6) alkyl, (C6-C
10) arylsulfonyl (C1-C
6) alkyl, hydroxyl (C1-C
6) alkyl, amino (C1-C
6) alkyl, (C1-C
6) alkyl amino (C1-C
6) alkyl, ((C1
-C
6) alkyl amino)2(C
1-C
6) alkyl, R9R
10NCO(C
1-C
6) alkyl or R9OCO(C
1
-C
6) alkyl, wherein R9And R10Be independently of one another: hydrogen, (C1-C
6) alkyl, (C6-
C
10) aryl (C1-C
6) alkyl and (C5-C
9) heteroaryl (C1-C
6) alkyl; R8For R11O or R11R
12N, wherein R11And R12Be independently of one another: hydrogen, (C1-C
6) alkyl, (C6-C
10) aryl (C1-C
6) alkyl and (C5-C
9) heteroaryl (C1-C
6) alkyl;
Perhaps R
1And R
2Form piperazinyl with the nitrogen-atoms that links to each other;
Perhaps R
1And R
2, perhaps R
9And R
10, perhaps R
11And R
12Form with the atom that links to each other respectively: azetidinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, indolinyl, iso-dihydro-indole-group, tetrahydric quinoline group, tetrahydro isoquinolyl, (C
1-C
6) acyl piperazine base, (C
1-C
6) alkylpiperazine base, (C
6-C
10) arylpiperazinyl, (C
5-C
9) the heteroaryl piperazinyl, or be selected from the bridge-type diaza-bicyclo alkyl ring of following groups:
Wherein r is 1,2 or 3,
M is 1 or 2;
P is 0 or 1; With
Q is hydrogen, (C
1-C
3) alkyl or (C
1-C
6) acyl group;
R
3And R
4Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, trifluoromethyl, trifluoromethyl (C
1-C
6) alkyl, (C
1-C
6) alkyl (difluoro methylene), (C
1-C
3) alkyl (difluoro methylene) (C
1-C
3) alkyl, (C
6-C
10) aryl, (C
5-C
9) heteroaryl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
5-C
9) heteroaryl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) acyloxy (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, piperazinyl (C
1-C
6) alkyl, (C
1-C
6) amido (C
1-C
6) alkyl, piperidyl, (C
1-C
6) the Alkylpiperidine base, (C
6-C
10) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
5-C
9) heteroaryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) alkylthio (C
1-C
6) alkyl, (C
6-C
10) aryl sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkyl sulfinyl (C
1-C
6) alkyl, (C
6-C
10) aryl sulfinyl (C
1-C
6) alkyl, (C
1-C
6) alkyl sulfonyl (C
1-C
6) alkyl, (C
6-C
10) arylsulfonyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, (C
1-C
6) alkylamino (C
1-C
6) alkyl, ((C
1-C
6) alkylamino)
2(C
1-C
6) alkyl, R
13CO (C
1-C
6) alkyl, wherein R
11Be R
20O or R
20R
21N, R
20Or R
21Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
5-C
9) heteroaryl (C
1-C
6) alkyl; Or R
14(C
1-C
6) alkyl, wherein R
14Be (C
1-C
6) the acyl piperazine subbase, (C
6-C
10) the aryl piperazines subbase, (C
5-C
9) the heteroaryl Piperazino, (C
1-C
6) alkyl piperazine sub-base, (C
6-C
10) aryl (C
1-C
6) alkyl piperazine sub-base, (C
5-C
9) heteroaryl (C
1-C
6) alkyl piperazine sub-base, morpholino, thiomorpholine generation, piperidino-(1-position only), pyrrolidino, piperidyl, (C
1-C
6) the Alkylpiperidine base, (C
6-C
10) Arylpiperidine base (C
5-C
9) the heteroaryl piperidine base, (C
6-C
10) aryl (C
1-C
6) the Alkylpiperidine base, (C
5-C
9) heteroaryl (C
1-C
6) Alkylpiperidine base or (C
1-C
6) the acylpiperidine base;
Perhaps R
3And R
4, perhaps R
20And R
21Form together: (C
3-C
6) cycloalkyl, Yang Za Evil cyclohexyl, sulfo-cyclohexyl, 2,3-indanyl or 1,2,3,4-tetralin basic ring, or following formula group
R wherein
15Be hydrogen, (C
1-C
6) acyl group, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
5-C
9) heteroaryl (C
1-C
6) alkyl or (C
1-C
6) alkyl sulphonyl; With
Ar is (C
6-C
10) aryl, (C
5-C
9) heteroaryl, (C
1-C
6) alkyl (C
6-C
10) aryl, (C
1-C
6) alkoxyl group (C
6-C
10) aryl, ((C
1-C
6) alkoxyl group)
2(C
6-C
10) aryl, (C
6-C
10) aryloxy (C
6-C
10) aryl, (C
5-C
9) heteroaryloxy (C
6-C
10) aryl, (C
1-C
6) alkyl (C
5-C
9) heteroaryl, (C
1-C
6) alkoxyl group (C
5-C
9) heteroaryl, ((C
1-C
6) alkoxyl group)
2(C
5-C
9) heteroaryl, (C
6-C
10) aryloxy (C
5-C
9) heteroaryl, (C
5-C
9) heteroaryloxy (C
5-C
9) heteroaryl;
But condition is to work as R
1Or R
2One of be CH (R
7) COR
8, R wherein
7And R
8When defining as above, another R
1Or R
2Be hydrogen, (C
1-C
6) alkyl, or benzyl.
Except as otherwise noted, term used herein " alkyl " comprises the saturated monovalence alkyl that has straight chain, side chain or loop section or their combination.
Term used herein " alkoxyl group " comprises the 0-alkyl, and wherein " alkyl " as above defines.
Except as otherwise noted, term used herein " aryl " comprises that by removing the organic group that hydrogen obtains from aromatic hydrocarbons for example phenyl or naphthyl can be replaced arbitrarily by 1-3 substituting group that is selected from following radicals: fluorine, chlorine, trifluoromethyl, (C
1-C
6) alkoxyl group, (C
6-C
10) aryloxy, trifluoromethoxy, difluoro-methoxy and (C
1-C
6) alkyl.
Except as otherwise noted, term used herein " heteroaryl " comprises the organic group that obtains from a heteroaromatic compounds hydrogen of removal, for example: pyridyl; furyl, pyrrolidine formyl base (pyroyl), thienyl; isothiazolyl, imidazolyl, benzimidazolyl-; tetrazyl, pyrazinyl, pyrimidyl; quinolyl, isoquinolyl, benzofuryl; isobenzofuran-base, benzothienyl, pyrazolyl; indyl, pseudoindoyl, purine radicals; carbazyl ， isoxazolyl, thiazolyl oxazolyl; benzothiazolyl, or benzoxazolyl can be replaced arbitrarily by 1-2 substituting group that is selected from following radicals: fluorine; chlorine; trifluoromethyl; (C
1-C
6) alkoxyl group, (C
6-C
10) aryloxy, trifluoromethoxy, difluoro-methoxy and (C
1-C
6) alkyl.
Except as otherwise noted, term used herein " acyl group " comprises that general formula is the group of RCO, and wherein R is an alkyl, alkoxyl group, and aryl, aralkyl, or aralkoxy, term " alkyl " or " aryl " as above define.
Term used herein " acyloxy " comprises the 0-acyl group, and wherein " acyl group " as above defines.
Formula I compound can have chiral centre, therefore has different enantiomeric forms, the present invention relates to all optical isomers and the steric isomer and their mixture of formula I compound.
Preferred formula I compound comprises that n wherein is those of 2.
Preferred formula I compound comprises that also Ar is those of 4-methoxyphenyl or 4-phenoxy phenyl.
Preferred formula I compound also comprises R
3Or R
4One of be not those of hydrogen.
Preferred formula I compound comprises that also n is 1, and R
1And R
2One of be those of hydrogen.
Preferred formula I compound comprises that also X is a hydroxyl, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, and R
3Or R
4One of be not those of hydrogen.
Preferred formula I compound comprises that also X is an alkoxyl group, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, and R
3Or R
4One of be not those of hydrogen.
Preferred formula I compound comprises that also Ar is 4-methoxyphenyl or 4-phenoxy phenyl, and R
3And R
4Form (C together
3-C
6) cycloalkyl group, amylene oxide base, sulfo-cyclohexyl, 2,3-indanyl or following formula group
R wherein
12Be (C
1-C
6) acyl group, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
5-C
9) heteroaryl (C
1-C
6) alkyl or (C
1-C
6) those of alkyl sulphonyl.
Preferred formula I compound is that n is 2, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, R
1And R
2Form piperazinyl together, (C
1-C
6) the alkylpiperazine base, (C
6-C
10) arylpiperazinyl, or (C
1-C
9) heteroaryl (C
1-C
6) the alkylpiperazine base, and R
3Or R
4One of be not hydrogen or R
3And R
4The two all is not hydrogen those.
Preferred formula I compound is that n is 2, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, R
1Be hydrogen or (C
1-C
6) alkyl, R
2Be 2-picolyl, 3-picolyl or 4-picolyl, and R
3Or R
4One of be not hydrogen or R
3And R
4The two all is not hydrogen those.
Preferred formula I compound is that n is 1, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, R
1Be hydrogen, R
2Be 2-picolyl, 3-picolyl or 4-picolyl, and R
3Or R
4One of be not hydrogen or R
3And R
4The two all is not hydrogen those.
Preferred formula I compound is that n is 2, and Ar is the 4-methoxyphenyl, R
1Be hydrogen or (C
1-C
6) alkyl, R
2Be R
5(C
2-C
6) alkyl, wherein R
5Be morpholino, thiomorpholine generation, piperidino-(1-position only), pyrrolidino, (C
1-C
6) the acyl piperazine subbase, (C
1-C
6) alkyl piperazine sub-base, (C
6-C
10) the aryl piperazines subbase, (C
5-C
9) the heteroaryl Piperazino, (C
6-C
10) aryl (C
1-C
6) alkyl piperazine sub-base, or (C
5-C
9) heteroaryl (C
1-C
6) alkyl piperazine sub-base, and R
3Or R
4One of be not hydrogen or R
3And R
4The two all is not hydrogen those.
Preferred formula I compound is that n is 1, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl, R
1Be hydrogen, R
2Be R
5(C
2-C
6) alkyl, wherein R
5Be morpholino, thiomorpholine generation, piperidino-(1-position only), pyrrolidino, (C
1-C
6) the acyl piperazine subbase, (C
1-C
6) alkyl piperazine sub-base, (C
6-C
10) the aryl piperazines subbase, (C
5-C
9) the heteroaryl Piperazino, (C
6-C
10) aryl (C
1-C
6) alkyl piperazine sub-base, or (C
5-C
9) heteroaryl (C
1-C
6) alkyl piperazine sub-base, and R
3Or R
4One of be not hydrogen or R
3And R
4The two all is not hydrogen those.
Particularly preferred formula I compound comprises:
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-3-methylbutyryl amine;
2-(R)-2-((2-benzylamino formyl radical ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-((pyridin-3-yl methyl) formamyl) ethyl) amino)-3-methylbutyryl amine;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-(picoline-3-ylmethyl formamyl) ethyl) amino)-3-methylbutyryl amine;
4-(3-(1-(R)-1-hydroxyl amino formyl radical-2-methyl-propyl) (4-methoxy benzene sulfonyl) amino) propionyl) piperazine-1-carboxylic acid, the tert-butyl ester;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-oxo-3-piperazine-1-base propyl group) amino)-3-methylbutyryl amine salt acidulants;
2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl)-((2-morpholine-4-base ethylamino formyl radical) methyl) amino)-3-methylbutyryl amine; With
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (((pyridin-3-yl methyl) formamyl) methyl) amino)-3-methylbutyryl amine.
Other concrete formula I compound comprises:
2-(R)-3,3,3-three fluoro-N-hydroxyl-2-((methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino) propionic acid amide;
2-(R)-N-hydroxyl-2-((4-benzene oxygen benzene sulfonyl) (2-(picoline-4-ylmethyl formamyl) ethyl) amino)-3-methylbutyryl amine;
4-(4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-1-methyl piperidylidene-4-hydroxyformamide;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl)-(3-(4-methylpiperazine-1-yl)-3-oxopropyl) amino)-3-methylbutyryl amine;
2-(R)-2-((2-propyloic) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
((2-propyloic) (3,4-dimethoxy-benzene sulphonyl) amino)-N-hydroxyl-ethanamide;
2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R), 3-(R)-3, N-dihydroxyl-2-((4-methoxy benzene sulfonyl) (3-oxygen-3-piperidines-1-base propyl group) amino)-butyramide;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-(picoline-3-ylmethyl formamyl) propyl group) amino)-3-methylbutyryl amine;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-(methyl carboxymethylamino formyl radical) ethyl) amino)-3-methylbutyryl amine;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl)-((1-methyl piperidine-4-base formamyl) methyl) amino)-3-methylbutyryl amine;
2-(R)-2-cyclohexyl-N-hydroxyl-2-((4-methoxy benzene sulfonyl)-(3-(4-methylpiperazine-1-yl)-3-oxopropyl) amino)-ethanamide;
2-(R)-N-hydroxyl-2-((methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-4-(morpholine-4-yl) butyramide.
The invention still further relates to the pharmaceutical composition that is used for following situation: (a) be used for following treatment of diseases: sacroiliitis, cancer, tissue ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other are the disease of characteristics with the matrix metal proteinase activity, acquired immune deficiency syndrome (AIDS), sepsis, septic shock and other relate to the disease of tumour necrosis factor (TNF) product, or (b) being used to comprise the inhibition of matrix metalloproteinase in people's the mammiferous body or tumour necrosis factor (TNF) product, this pharmaceutical composition is made up of claim 1 compound of significant quantity in such treatment or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
The invention still further relates to (a) matrix metalloproteinase in the mammalian body that suppresses to comprise the people, or (b) method of tumour necrosis factor (TNF) product, this method comprises claim 1 compound or its pharmacy acceptable salt that gives described Mammals significant quantity.
The invention still further relates to the mammiferous sacroiliitis that comprises the people, cancer, tissue ulcer, restenosis, periodontal disease, epidermolytic bulla, scleritis and other and with the matrix metal proteinase activity be the methods of treatment of the disease, acquired immune deficiency syndrome (AIDS), sepsis, septic shock of characteristics and other disease that relates to tumour necrosis factor (TNF) product etc., this method comprises claim 1 compound or its pharmacy acceptable salt that gives described Mammals significant quantity in to such treatment of diseases.
Detailed description of the present invention
Following reaction stream formula has been illustrated the preparation process of The compounds of this invention.Except as otherwise noted, in reaction stream formula and detailed argumentation subsequently, R
1, R
2, R
3, R
4, n and Ar all as defined above.
Flow process 1
Flow process 1 (continuing)
Flow process 2
Flow process 3
Flow process 4
Flow process 4 (continuing)
In flow process
1Reaction 1 in, the amino-acid compound of formula VII, wherein R
16Be (C
1-C
6) alkyl, benzyl, allyl group or the tertiary butyl, be converted into corresponding formula VI compound by active functional derivative such as aryl sulfonyl chloride reaction with the aryl sulfonic acid compound, this reaction is under the condition of alkali such as triethylamine existence, at polar solvent such as tetrahydrofuran (THF), diox, water or acetonitrile, carry out in the mixture of You Xuan diox and water.This reaction mixture is stir about 10 minutes at room temperature---and about 24 hours, preferred about 60 minutes.
In flow process
1Reaction 2 in, the aryl sulphonyl amino based compound of formula VI, wherein R
16Be (C
1-C
6) alkyl, benzyl, allyl group or the tertiary butyl, by with the reactive derivative of following formula alcohol such as chlorine, bromine or iodine derivative, preferred br-derivatives reaction and be converted into corresponding formula V compound, wherein n is 1,3,4,5 or 6,
R wherein
17Protecting group is (C
1-C
6) alkyl, benzyl, allyl group or the tertiary butyl.This reaction is at alkali such as salt of wormwood or sodium hydride, under the condition that preferred sodium hydride exists, carries out in as dimethyl formamide at polar solvent.This reaction mixture is stir about 60 minutes about 48 hours at room temperature, preferred about 18 hours.Select R
17During protecting group, make it at R
16Optionally remove under the situation that protecting group exists, and can not lose R
16Protecting group, so R
17Can not with R
16Identical.In flow process
1Reaction 3 in, remove R from formula V compound
17Protecting group obtains corresponding formula IV carboxylic acid, and this reaction is to use specific R
17Can not influence R during protecting group
16Carry out under the suitable condition of protecting group.Such condition comprises: (a) R
17Be (C
1-C
6) alkyl, R
16Saponification during for the tertiary butyl, (b) R
17Be benzyl, R
16Be the tertiary butyl or (C
1-C
6) hydrogenolytic cleavage during alkyl, (c) R
17Be the tertiary butyl, R
16Be (C
1-C
6) handle with strong acid such as trifluoroacetic acid or hydrochloric acid when alkyl, benzyl or allyl group, or (d) R
17Be allyl group, R
16Be (C
1-C
6) when alkyl, benzyl or the tertiary butyl, under the condition that two (triphenylphosphine) Palladous chlorides (II) of catalysis exist, handle with tributyltin hydride and acetate.
In flow process
1Reaction 4 in, the carboxylic acid of formula IV and amine, R
1R
2NH or their salt condensation obtain the amide compound of corresponding formula III.If will begin to generate amide compound, can be converted into behind the active functional derivative again with uncle or secondary amine or ammonia react by carboxylic acid and generate acid amides from primary amine or secondary amine or ammonia and carboxylic acid.This active functional derivative can with uncle or secondary amine or ammonia react before separate earlier.On the other hand; carboxylic acid can be pure or in inert solvent such as chloroform, at about 25 ℃-Yue 80 ℃, under preferred about 50 ℃; handle to obtain corresponding chloride of acid functional derivatives with oxalyl chloride or thionyl chloride, inert solvent and any oxalyl chloride that retains or thionyl chloride are removed in vacuum-evaporation then.Remaining chloride of acid functional derivatives reacts the generation acid amides with primary amine or secondary amine or ammonia again in inert solvent such as methylene dichloride.The carboxylic acid of preferred formula IV and the method that the amine condensation obtains the amide compound of corresponding formula III are: on-the-spot disposal IV under the condition of alkali such as triethylamine existence obtains benzotriazole-1-oxygen ester with phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus, it more at room temperature, in inert solvent such as methylene dichloride, successively with amine, R
1R
2The N reaction obtains the amide compound of formula III.
In flow process
1Reaction 5 in, remove R from the formula III compound
16Protecting group obtains corresponding formula II carboxylic acid.This reaction is to used specific R
16Carry out under the condition that protecting group suits.Such condition comprises: (a) R
16Saponification during for low alkyl group, (b) R
16Hydrogenolytic cleavage during for benzyl, (c) R
16Handle with strong acid such as trifluoroacetic acid or hydrochloric acid during for the tertiary butyl, or (d) R
16During for allyl group, under the condition that two (triphenylphosphine) Palladous chlorides (II) of catalysis exist, handle with tri-butyl tin hydride and acetate.
In flow process
1Reaction 6 in, formula II carboxylic acid cpd is in polar solvent such as dimethyl formamide, handle with 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and I-hydroxybenzotriazole and be converted into the hydroxamic acid compound of formula I, about 15 minutes one about 1 hour, preferred after about 30 minutes, in this reaction mixture, add azanol.Azanol is preferably made from salt pattern example hydrochloric acid azanol under the condition of alkali such as N-methylmorpholine existence on the spot.On the other hand, the protected quilt for the azanol of the tertiary butyl, benzyl or allyl ethers or its salt pattern of hydroxyl protects derivative and can use under the condition that phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus and alkali such as N-methylmorpholine exist.Can remove benzyl protecting group in the azanol protecting group by hydrogenolytic cleavage, or handle to remove tertiary butyl protecting group with strong acid such as trifluoroacetic acid.Allyl-based protection can be removed by handling with tri-butyl tin hydride and acetate under the condition that exists at two (triphenylphosphine) Palladous chlorides (II) of catalysis.N, two (4-methoxybenzyl) azanols of O-also can be used as protected hydroxylamine derivative, at this moment can utilize the mixture of methylsulfonic acid and trifluoroacetic acid to go protection.
In flow process
2Reaction 1 in, the aryl sulphonyl amino based compound of formula VI, wherein R
16Be (C
1-C
6) alkyl, benzyl or the tertiary butyl, be converted into corresponding formula VIII compound, wherein R
18Be 2-propenyl or 3-butenyl.Work as R
18During for the 2-propenyl, this step is active functional derivative such as the halogenide by IX and 2-propylene-1-alcohol, and preferred iodine derivatives reaction is finished; Work as R
18During for the 3-butenyl, this step is active functional derivative such as the halogenide by IX and 3-butene-1-alcohol, and preferred iodine derivatives reaction is finished, and these reactions are all carried out in the presence of alkali such as salt of wormwood, cesium carbonate or sodium hydride, work as R
18During for the 2-propenyl, preferred sodium hydride is worked as R
18During for the 3-butenyl, preferred cesium carbonate.This reactant at room temperature, stir about is 2 hours-Yue 48 hours in polar solvent such as dimethyl formamide, preferred about 18 hours.
In flow process
2Reaction 2 in, formula VIII compound is converted into the carboxylic acid cpd of formula IV, wherein n is 2.R
18For the VIII compound of 2-propenyl by with borane-diformazan sulfide title complex reaction after in aqueous acetic acid, carry out oxidation immediately and be converted into formula IV compound with chromium trioxide, wherein n is 2.The terminal olefine oxicracking is that carboxylic acid can be finished by the whole bag of tricks that those of ordinary skills know.R
18The preferred method that obtains the carboxylic acid cpd of formula IV for the VIII compound oxidation cracking of 3-butenyl is: react under the condition that the ruthenium chloride (III) of VIII and the sodium periodate catalytic amount in the mixture that is present in tetracol phenixin, acetonitrile and water exists.
According to above-mentioned flow process
1Reaction 4,5 and 6 described in method, formula IV compound, wherein n is 2, further reaction obtains the hydroxamic acid compound of formula I, wherein n is 2.
In flow process
3Reaction 1 in, shown the hydroxamic acid compound of formula I, wherein n is 1 and R
3And R
4Be hydrogen, synthetic method, this method is functional derivatives such as the aryl sulfonyl chloride from the metal of the acetimidic acid of formula X or acetimidic acid or ammonium salt and aryl sulfonic acid compound, at room temperature, suitable alkali such as triethylamine and polar solvent such as tetrahydrofuran (THF), diox, water or acetonitrile react in the mixture of You Xuan diox and water that the dicarboxylic acid compound that obtains corresponding formula XI begins.
In flow process
3Reaction 2 in, the dehydration of the dicarboxylic acid compound of formula XI obtains the cyclic anhydride compound of formula XII.Dicarboxylic acid compound forms the cyclic anhydride compound by dehydration and can realize with multiple mode.The method that the dicarboxylic acid compound dehydration of preferred formula XI obtains the cyclic anhydride compound of formula XII is: at about 25 ℃-Yue 80 ℃, under preferred about 60 ℃, handle XI with the excessive acetic acid acid anhydride, behind evaporation under reduced pressure removed excessive acetic acid acid anhydride and byproduct of reaction acetate, obtain the cyclic anhydride compound of formula XII.
In flow process
3Reaction 3 in, the cyclic anhydride compound of formula XII at room temperature with amine, NR
1R
2, or the salt example hydrochloric acid salt of amine, under the condition that alkali such as triethylamine exist, react the carboxylic acid that obtains formula II, wherein n is 1 and R
3And R
4Be hydrogen.The suitable solvent that is used for this reaction be not can with those of initiator reaction, comprising: chloroform, methylene dichloride and dimethyl formamide, preferred methylene dichloride.
According to above-mentioned flow process
1Reaction 6 described in method, formula II compound further reaction obtains the hydroxamic acid compound of formula I, wherein n is 1 and R
3And R
4Be hydrogen.
In flow process
4Reaction 1 in, the carboxylic acid cpd of formula IV, wherein n is 2, by with formula: (R
19O)
2CHN (CH
3)
2, R wherein
19Be (C
1-C
6) compound of alkyl or the tertiary butyl in inert solvent such as toluene, at about 60 ℃-Yue 100 ℃, preferred about 100 ℃ of reactions about 1 hour-Yue 3 hours down, preferred 2 hours, thus be converted into corresponding formula V compound, R wherein
19Be (C
1-C
6) alkyl or the tertiary butyl.In flow process
4Reaction 2 in, the aryl sulphonyl amino based compound of formula VI, wherein n is 1,3,4,5 or 6, and R
16Be (C
1-C
6) alkyl, benzyl, allyl group or the tertiary butyl, by with the reactive derivative of following formula alcohol such as chlorine, bromine or iodine derivative, preferred br-derivatives reaction and be converted into corresponding formula VIII compound, wherein R
19Be (C
1-C
6) alkyl or the tertiary butyl
R wherein
19Be (C
1-C
6) alkyl or the tertiary butyl.This reaction is at alkali such as salt of wormwood or sodium hydride, under the condition that preferred sodium hydride exists, carries out in as dimethyl formamide at polar solvent.This reactant is stir about 60 minutes-Yue 48 hours at room temperature, preferred about 18 hours.The R of selecting type IV and formula VI compound
16During protecting group, make it at R
19(C
1-C
6) optionally remove under alkyl or the tertiary butyl situation about existing, and can not lose R
19(C
1-C
6) alkyl or the tertiary butyl, so R
16Can not with R
19Identical.In flow process
4Reaction 3 in, remove R from formula VIII compound
16Protecting group obtains the carboxylic acid of corresponding formula XIV, and wherein n is 1-6, and this reaction is to use specific R
16Can not influence R during protecting group
19(C
1-C
6) carry out under the suitable condition of alkyl or the tertiary butyl.Such condition comprises: (a) R
16Be (C
1-C
6) alkyl, R
19Saponification during for the tertiary butyl, (b) R
16Be benzyl, R
19Be the tertiary butyl or (C
1-C
6) hydrogenolytic cleavage during alkyl, (c) R
16Be the tertiary butyl, R
19Be (C
1-C
6) handle with strong acid such as trifluoroacetic acid or hydrochloric acid during alkyl, or (d) R
16Be allyl group, R
19Be (C
1-C
6) when alkyl or the tertiary butyl, under the condition that two (triphenylphosphine) Palladous chlorides (II) of catalysis exist, handle with tributyltin hydride and acetate.
In flow process
4Reaction 4 in, formula XIV carboxylic acid is in polar solvent such as dimethyl formamide, handle with 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide and 1-1-Hydroxy Benzotriazole and be converted into the hydroxamic acid compound of formula XV, wherein n is 1-6, about 15 minutes-Yue 1 hour, preferred after about 30 minutes, in this reaction mixture, add azanol.Azanol is preferably made from salt pattern example hydrochloric acid azanol under the condition of alkali such as N-methylmorpholine existence on the spot.On the other hand, the protected quilt for the azanol of the tertiary butyl, benzyl or allyl ethers or its salt pattern of hydroxyl protects derivative and can use under the condition that phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus and alkali such as N-methylmorpholine exist.Can remove benzyl protecting group in the azanol protecting group by hydrogenolytic cleavage, or handle to remove tertiary butyl protecting group with strong acid such as trifluoroacetic acid.Allyl-based protection can be removed by handling with tri-butyl tin hydride and acetate under the condition that exists at two (triphenylphosphine) Palladous chlorides (II) of catalysis.Work as R
19Be (C
1-C
6) during alkyl, N, two (4-methoxybenzyl) azanols of O-also can be used as and protected hydroxylamine derivative, at this moment can utilize the mixture of methylsulfonic acid and trifluoroacetic acid to go protection.
In flow process
4Reaction 5 in, if need, the acid amides of formula XV can pass through: (a) R
19Saponification during for low alkyl group, or (b) R
19Handle the carboxylic acid cpd that is converted into corresponding formula XVI with strong acid such as trifluoroacetic acid or hydrochloric acid during for the tertiary butyl.
The pharmacy acceptable salt of acidic cpd of the present invention is the salt that forms with alkali, i.e. cationic salts such as basic metal and alkaline earth salt, for example sodium, lithium, potassium, calcium, magnesium and ammonium salt such as ammonium, trimethyl ammonium, diethyl ammonium and three-(methylol)-methyl ammonium salt.
The acid salt of the salt of mineral acid, organic carboxyl acid and the organic sulfonic acid of same all example hydrochloric acids, methylsulfonic acid, toxilic acid etc. also may provide the component part of structure, the basic group as pyridyl.
Shown formula I compound or their pharmacy acceptable salt (hereinafter also being referred to as The compounds of this invention) inhibition ability by the test of following analyzed in vitro, therefore proved them to being that the treatment of diseases of feature is renderd a service with matrix metalloproteinase or tumour necrosis factor product matrix metalloproteinase or tumour necrosis factor (TNF) product.
Biological analysis is measured
The inhibition of human collagenase (MMP-1)
According to following ratio with trypsinase human activin recombinant chou collagenase: 10 μ g trypsinase/100 μ g collagenases.This trypsinase and collagenase were at room temperature cultivated 10 minutes, added 5 times of amounts (50 μ g/10 μ g trypsinase) Trypsin inhibitor SBTI then.
The 10mM liquid storage of preparation inhibitor dilutes according to following process: 10mM---＞120 μ M---＞12 μ M---＞1.2 μ M---＞0.12 μ M then in methyl-sulphoxide
25 microlitre liquid storages of every kind of concentration are triplicate, add respectively in the suitable groove of 96 groove microscopic fluorescence plates.Added that inhibitor is that final concentration is 1: 4 diluent behind enzyme and the substrate.Positive control (enzyme being arranged, the unrestraint agent) places groove D1-D6, and blank (no enzyme, unrestraint agent) places groove D7-D12.
After collagenase is diluted to 400ng/ml, 25 μ L are added in the suitable groove of microscopic fluorescence plate.The final concentration of collagenase is 100ng/ml in the test.
With methyl-sulphoxide with substrate (DNP-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMA)-NH
2) be mixed with the 5mM liquid storage, be diluted to 20 μ M with assay buffer then.Adding 50 μ L substrates in each groove of microscopic fluorescence plate, to make final concentration be 10 μ M, begins test thus.
In the time is 0 o'clock record fluorescence reading (360nM excites, the 460nm emission), later on every 20 minutes records once.This test was at room temperature carried out 3 hours.
Afterwards, mark and draw the ratio (these data are average detected values of three duplicate samples) of the fluorescence of blank and the collagenase that contains sample to the time.Selection can obtain the time point of good signal (blank) and the linear portion on the curve (usually about 120 minutes) time corresponding point to measure IC
50Value.0 o'clock value is as the blank of each compound under every kind of concentration, and these values are deducted the data during from 120 minutes.Depict the result per-cent (only use fluorescence * 100 of collagenase separate inhibitor fluorescence) of inhibitor concentration as to contrast concentration.IC
50Inhibitor concentration when value is 50% signal that obtains contrasting.
If the IC of report
50Value＜0.03 μ M then detects inhibitor under the concentration of 0.3 μ M, 0.03 μ M, 0.03 μ M and 0.003 μ M.
The inhibition of gelatinase (MMP-2)
Under the same terms that suppresses with human collagenase (MMP-1), utilize Dnp-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMA)-NH
2Substrate (10 μ M) detects the active inhibition of gelatinase.
Under 4 ℃, with 1mM APMA (equal amido phenenyl acid mercury) activation 72kD gelatinase 15 hours and with its dilution, making its final concentration in test is 100mg/ml.As human collagenase (MMP-1) suppressed, it was 30 μ M, 3 μ M, 0.3 μ M and 0.03 μ M that inhibitor is diluted to its final concentration in test.Three parts of every kind of concentration specimen preparations.
In the time is 0 o'clock record fluorescence reading (360nm excites, the 460nm emission), every 20 minutes records once, carries out altogether 4 hours later on.
IC when measuring each human collagenase (MMP-1) inhibition
50Value.If the IC of report
50Value then detects inhibitor less than 0.03 μ M under the final concentration of 0.3 μ M, 0.03 μ M, 0.003 μ M and 0.003 μ M.
The inhibition of stromelysin activity (MMP-3)
The active inhibition of stromelysin is that (J. is used for the Spectrophotometric Assays method of vertebrate collagenase, analytical biochemistry for Weingarten, H. and Feder for the improved Spectrophotometric Assays method described with Weingarten and Feder
147, 437-440 (1985)) and be basic.Sulfo-peptolide substrate (Ac-Pro-Leu-Gly-SCH[CH
2CH (CH
3)
2] CO-Leu-Gly-OC
2H
5) hydrolysis obtain can be under the condition that Ellman s reagent exists monitored mercaptan fragment.
With the ratio of 1 μ L 10mg/ml trypsinase liquid storage/26 μ g stromelysins, with the former stromelysin prostromelysin of trypsinase human activin recombinant chou.With this trypsinase and stromelysin 37 ℃ of following incubations 15 minutes, add 10 μ L 10mg/ml Trypsin inhibitor SBTIs then and 37 ℃ of following incubations 10 minutes with the deactivation tryptic activity.
(200mM sodium-chlor, 50mM MES and 10mM calcium chloride carry out in pH6.0) in 96 groove microlitre plates and cumulative volume 250 μ L assay buffer in test.With assay buffer active stromelysin is diluted to 25 μ g/ml.With dimethyl formamide Ellman s reagent (3-carboxyl-4-pyridyl disulphide) is mixed with the 1M liquid storage, every then groove is diluted to 5mM with 50 μ L assay buffer, and obtaining final concentration is 1mM.
Prepare the 10mM liquid storage of inhibitor with methyl-sulphoxide, and with the assay buffer serial dilution so that obtain final concentration 3 μ M, 0.3 μ M, 0.003 μ M and 0.0003 μ M after in suitable groove, adding 50 these liquid of μ L.Carry out in triplicate under all conditions.
With assay buffer the 300mM methyl-sulphoxide liquid storage of peptide substrates is diluted to 15mM, to obtain final concentration be the 3mM substrate by add 50 μ L in every groove, begins test thus.Blank by peptide substrates and the Ellman s reagent that does not contain enzyme constitute.With of the formation of minute subset UVmax plate readout instrument at 405nm monitoring product.
Measure IC with the same procedure that collagenase is used
50Value.
The inhibition of MMP-13
With 2mM APMA (equal amido phenenyl acid mercury) 37 ℃ of following activating human body recombinant chou MMP-13 one and a half hours, and with assay buffer (50mM Tris, pH7.5,200mM sodium-chlor, 5mM calcium chloride, 20 μ M zinc chloride, 0.02% brij) it is diluted to 400mg/ml.In every groove of 96 groove microscopic fluorescence plates, add 25 microlitres dilution enzyme.This enzyme is diluted to final concentration is 100mg/ml by add inhibitor and substrate with 1: 4 ratio then.
Prepare the 10mM liquid storage of inhibitor with methyl-sulphoxide, the dilution of every kind of inhibitor is diluted with assay buffer in suppressing according to human collagenase (MMP-1) then: 25 microlitre samples of every kind of concentration are added the microscopic fluorescence plate in triplicate respectively.Final concentration in the test is 30 μ M, 3 μ M, 0.3 μ M and 0.03 μ M.
According to preparing substrate (Dnp-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMA)-NH in human collagenase (MMP-1) inhibition
2), and adding 50 μ L are 10 μ M to obtain final test concentration in every groove.In the time is 0 o'clock record fluorescence reading (360nm excites, the 450nm emission), every 5 minutes records once, carries out altogether 1 hour later on.
Positive control is by enzyme and do not have the substrate of inhibitor to constitute, and blank only is made of substrate.
Suppress used same procedure according to human collagenase (MMP-1) and measure IC
50Value.If the IC of report
50Value then detects inhibitor less than 0.03 μ M under the final concentration of 0.3 μ M, 0.03 μ M, 0.003 μ M and 0.0003 μ M.
The inhibition of TNF product
The compounds of this invention or its pharmacy acceptable salt suppress the ability of TNF product, and the treatment that they have and the effectiveness of TNF product diseases associated are proved by following in vitro tests:
From anticoagulant human blood, separate the human body monocyte with single step Ficollhypaque operative technique, after these monocytes wash three times with the Hanks balanced salt solution (HBSS) that has divalent cation, again with 2 * 10
6The density of/ml is suspended among the HBSS that contains 1%BSA.The different readings that record with Abbott CellDyn 3500 analysers show the monocyte that 17-24% is arranged in total cell of these goods.
With 180 μ cell suspension five equilibriums at the bottom of the plate of 96 frids (Costar).It is 200 μ L that adding The compounds of this invention and LPS (final concentration 100ng/ml) make final volume.All carry out in triplicate under all conditions.At moistening CO
2In the incubator, under 37 ℃, cultivate after 4 hours, remove plate and centrifugal (with centrifugal 10 minutes of the speed of about 250 * g) after, remove supernatant liquor, use R﹠amp; D ELISA Kit measures TNF α.
When with these medicine administration of human when suppressing matrix metalloproteinase or tumour necrosis factor (TNF) product, can use the number of ways that comprises oral, parenteral route and topical.In general, the dosage during the oral or parenteral administration of active compound is about 0.1-25mg/kg body weight every day, preferably about 0.3-5mg/kg.Yet, must do some adjustment to dosage according to treatment patient's the different state of an illness.Under any circumstance, the people of responsible administration should determine each patient's suitable dose.
In general, the different unit dosage administrations that The compounds of this invention can wide region, the concentration of medicable compound of the present invention in such unit dosage is about 5.0%-about 70% (weight).
For oral administration, can contain various vehicle such as Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine in the tablet, also can contain various disintegrating agents such as starch (preferred W-Gum, potato starch or tapioca (flour)), alginic acid and some composition silicate simultaneously, particle binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, usually for tablet very usefully wetting agent such as Magnesium Stearate, sodium lauryl sulphate and talcum.The solids composition of kindred type also can be used as the weighting agent in the gelatine capsule, and preferred material also comprises lactose or toffee and high-molecular weight polyoxyethylene glycol in these situations.When hope during with aq suspension and/or elixir oral administration, activeconstituents can combine with various sweeting agents or seasonings, coloring material or dyestuff, if desired, also emulsifying agent and/or suspension agent be can add, and thinner and their various combinations such as water, ethanol, propylene glycol, glycerine resembled.
For parenteral administration (intramuscular injection, peritoneal injection, subcutaneous injection and intravenous injection), prepare the aseptic parenteral solution of activeconstituents usually.Be sesame or the peanut oil solution that available the present invention treats compound, also available its aqueous propylene glycol solution.If desired, the aqueous solution should carry out suitable adjustment and buffering, and preferred pH value at first will become liquid diluent isoosmotic greater than 8.The intravenous injection that suits of these aqueous solution.Also available oily solution for intra-articular injection, intramuscular injection and subcutaneous injection.The standard pharmaceutical technology that the preparation of all these solution under aseptic condition is easy to utilize those of ordinary skills to know is finished.
Utilize following embodiment can further illustrate the present invention, but never play any restriction.
Embodiment 1
2-(R)-N-hydroxyl-((methoxy benzene sulfonyl) (2-morpholine-4-base-2
-oxoethyl) amino)-3-methylbutyryl amine
To hydrochloric acid D-Xie Ansuan benzyl ester (2.4g, 10mmol) and triethylamine (2.5g, 3.5mL, water 25mmol) (50mL) and 1, add in 4-diox (50mL) solution 4-methoxy benzene sulfonyl chloride (2.3g, 11mmol).This mixture at room temperature stirred 1 hour, and vacuum is steamed and removed most of solvent then.With using dilute hydrochloric acid solution, water and salt water washing successively after the ethyl acetate dilution.Organic solution concentrates after with dried over mgso and obtains N-(4-methoxy benzene sulfonyl)-D-Xie Ansuan benzyl ester, is white solid, 3.6g (97%); M.p.92-94 ℃.
With N-(4-methoxy benzene sulfonyl)-D-Xie Ansuan benzyl ester (1.50g, 4.0mmol) add sodium hydride (0.1g, in anhydrous dimethyl formamide 4.2mmol) (20mL) suspension, after 30 minutes, add bromo-acetic acid tert-butyl (0.8mL, 4.2mmol).The gained mixture at room temperature stirs and spends the night, and adds saturated ammonium chloride (3mL) solution termination reaction then.Vacuum is steamed and is removed dimethyl formamide.Resistates is dissolved in water and salt water washing after the ethyl acetate.After dried over mgso, steaming removes ethyl acetate and obtains oily matter, utilize flash chromatography, use silicagel column, hexane liquid wash-out with 15% ethyl acetate obtains clean oil 2-(R)-2-(tert-butoxycarbonylmethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (1.92g, 98%) to separate from this oily matter.
(1.92g adds trifluoroacetic acid (7mL) in methylene dichloride 3.9mmol) (28mL) cold (0 ℃) solution to 2-(R)-2-(tert-butoxycarbonylmethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate.Gained solution is heated to room temperature and stirs and spend the night.Vacuum obtains 2-(R)-2-(carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate after steaming and removing methylene dichloride and trifluoroacetic acid, is transparent oily matter, 1.70g (100%).
To 2-(R)-2-(carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (573mg, 1.32mmol) methylene dichloride (12mL) solution in order add triethylamine (0.46mL, 3.28mmol), morpholine (0.127mL, 1.46mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (64 6mg, 1.46mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is with 0.5N hydrochloric acid soln and salt water washing, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography obtains 2-(R)-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-oxoethyl) amino)-benzyl 3-methylbutyrate with the hexane liquid wash-out of 40% ethyl acetate, is transparent oily matter, 590mg (89%).
(590mg adds 10% palladium carbon (200mg) in ethanol 1.17mmol) (50mL) solution to 2-(R)-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-oxoethyl) amino)-benzyl 3-methylbutyrate.This mixture stirred 2 hours under the 3 normal atmosphere hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains white foam shape thing 2-(R)-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino)-3 Methylbutanoic acid behind the evaporating solvent, 485mg (100%).
To 2-(R)-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino)-3 Methylbutanoic acid (485mg, 1.17mmol) methylene dichloride (12mL) solution in order add triethylamine (0.52mL, 3.71mmol), 0-benzyl oxammonium hydrochloride (205mg, 1.28mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (570mg, 1.29mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is used 0.5N hydrochloric acid soln, water, saturated sodium bicarbonate solution and salt water washing successively, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography obtains 2-(R)-N-benzyloxy-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino)-3-methylbutyryl amine with the acetic acid ethyl fluid wash-out of 20% hexane, is white foam shape thing, 510mg (84%).
(510mg adds 5% palladium carbon (120mg) in methyl alcohol 0.98mmol) (50mL) solution to 2-(R)-N-benzyloxy-2-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino)-3-methylbutyryl amine.This mixture stirred 2 hours under the 2 air pressure hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains 2-(R)-N-hydroxyl-2-(methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino behind the evaporating solvent)-3-methylbutyryl amine, be white solid, 418mg (99%);
1H NMR (CDCL
3): δ 10.3 (br s, 1H), 7.90 (br s, 1H, overlapping), 7.86 (d, J=8.8Hz, 2H, overlapping), 6.94 (d, J=8.8Hz, 2H), 4.39 (d, J=17.1Hz, 1H), 4.09 (d, J=17.1Hz, 1H), 3.84 (s, 3H), 3.80-3.48 (m, 9H), 2.20-1.95 (m, 1H), 0.82 (d, J=6.5Hz, 3H), 0.45 (d, J=6.5Hz, 3H); MS (LSIMS): m/z 430 (M+H).
Embodiment 2
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-
The 3-oxopropyl) amino)-3-methylbutyryl amine
To N-(4-methoxy benzene sulfonyl)-D-Xie Ansuan benzyl ester (2.2g, add in dry dimethyl formamide (40mL) solution 5.83mmol) cesium carbonate (2.3g, 7.1mmol) and 1-iodo-3-butylene (1.3g, 7.1mmol).This mixture at room temperature stirs to spend the night and falls back.With extracted with diethyl ether twice, the ether extraction liquid salt water washing after the merging, dried over mgso and concentrating under reduced pressure.Resistates is dissolved in 20% ethyl acetate/hexane; Crystalline initiator N-from this mixture (4-methoxy benzene sulfonyl)-D-Xie Ansuan benzyl ester (1.5g) passes through filtered and recycled.The filtrate vacuum concentration, the resistates silica gel column chromatography is an elutriant with 20% ethyl acetate/hexane, obtains 2-(R)-2-(fourth-3-thiazolinyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate, is transparent oily matter, 404mg (16%).
To 2-(R)-2-(fourth-3-thiazolinyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (780mg, 1.81mmol) and ruthenium chloride (III) hydrate (10mg, 0.048mmol) add in the mixture in acetonitrile (6mL), tetracol phenixin (6mL) and water (8mL) sodium periodate (1.7g, 7.9mmol).After at room temperature stirring 2 hours, this mixture is with the methylene dichloride dilution and use diatomite filtration.Separate organic layer,, concentrate and obtain oily matter 2-(R)-2-(2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate, 710mg (87%) with dilute hydrochloric acid solution and salt water washing, dried over mgso.
In addition, available following high-yield process prepares intermediate product 2-(R)-2-(2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate:
With N-(4-methoxy benzene sulfonyl)-D-Xie Ansuan benzyl ester (18.8g, 49.8mmol) add sodium hydride (1.3g, in dry dimethyl formamide (200mL) suspension 54mmol), after 1.5 hours, add allyl bromide 98 solution (4.7mL, 54mmol).The gained mixture at room temperature stirs and spends the night, and adds the saturated ammonium chloride solution termination reaction then.Vacuum is steamed and is removed dimethyl formamide.Resistates is dissolved in water and salt water washing behind the ether.After dried over mgso, steaming removes ether and obtains oily matter, utilize flash chromatography, use silicagel column, behind the hexane liquid wash-out with 10% ethyl acetate, use the hexane liquid wash-out of 20% ethyl acetate again, obtain clarified oil 2-(R)-2-((4-methoxy benzene sulfonyl) third-2-alkenyl amino)-benzyl 3-methylbutyrate (18.1g, 87%) thereby from this oily matter, separate.
1M dichloromethane solution (1.45mL, 2.9mmol) middle 2-(R)-2-((4-methoxy benzene sulfonyl) third-2-alkenyl amino)-benzyl 3-methylbutyrate (3.6g, methylene dichloride 8.6mmol) (8mL) solution that adds to borane/disulphide title complex.This solution at room temperature stirred 4 hours, and the 1M dichloromethane solution of the borane/disulphide title complex of continuation adding during this period of time (2.0mL, 4.0mmol).This mixture at room temperature stirs and spends the night, and (5.1g, the 51.6mole) solution in acetate (31mL) and water (3.5mL) keeps internal temperature simultaneously between-5 ℃ to 10 ℃ dropwise to add churned mechanically chromium trioxide then.After this mixture at room temperature stirred and spends the night, dilute with water was also used dichloromethane extraction.Extraction liquid salt water washing, (sal epsom) dry back concentrates.Resistates also obtains oil with the chloroform solution wash-out of chloroform and 2% methyl alcohol successively with silica gel column chromatography: 2-(R)-2-(2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (2.42g, 63%).
To 2-(R)-2-(2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (710mg, 1.58mmol) methylene dichloride (15mL) solution in order add triethylamine (0.47mL, 3.35mmol), morpholine (0.15mL, 1.72mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (769mg, 1.74mmol).This mixture at room temperature stirs the back of spending the night and dilutes with methylene dichloride.This solution is with 0.5N hydrochloric acid soln and salt water washing, with dried over mgso and vacuum concentration.The solid residue silica gel column chromatography obtains 2-(R)-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-benzyl 3-methylbutyrate with the acetic acid ethyl fluid wash-out of 20% hexane, is transparent oily matter, 725mg (88%).
(725mg adds 10% palladium carbon (50mg) in ethanol 1.40mmol) (35mL) solution to 2-(R)-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-benzyl 3-methylbutyrate.This mixture stirred 3 hours under the 3 normal atmosphere hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains white solid 2-(R)-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-3 Methylbutanoic acid behind the evaporating solvent, 540mg (90%).
To 2-(R)-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-3 Methylbutanoic acid (540mg, 1.26mmol) and 1-1-Hydroxy Benzotriazole hydrate (205mg, 1.33mmol) anhydrous dimethyl formamide (12mL) solution in add hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (289mg, 1.51mmol).Stir after 30 minutes, the order add oxammonium hydrochloride (350mg, 5.04mmol) and triethylamine (1.0mL, 7.17mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is water, 0.5N hydrochloric acid soln and salt water washing successively, obtains white foam shape thing with dried over mgso and vacuum concentration.This material is dissolved in toluene, filters and concentrate.Resistates grinds with ether and obtains 2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-morpholine-4-base-3-oxopropyl) amino)-3-methylbutyryl amine, solid, 200mg (36%);
1H NMR (CDCL
3): δ 9.35 (br s, 1H), 7.73 (d, J=8.9Hz, 2H), 6.95 (d, J=8.9Hz, 2H), 3.86 (s, 3H), 3.83-3.73 (m, 1H), 3.70-3.52 (m, 7H), 3.46-3.43 (m, 2H), and 3.41-3.29 (m, 1H), 2.92-2.69 (m, 2H), 2.30-2.17 (m, 1H), 0.84 (d, J=6.5Hz, 3H), 0.41 (d, J=6.5Hz, 3H); MS (particle beam): m/z 444 (M+H), 428,383,329; The HRMS theoretical value is: C
19H
30N
3O
7S (M+H): 444.1804, actual recording: 464.1818.
With the similar approach of describing among the embodiment 2, so that (2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate is an initiator with following amine bonded 2-(R)-2-, the title compound of preparation embodiment 3-6.
Embodiment 3
2-(R)-2-((2-benzylamino formyl radical ethyl) (4-methoxy benzene sulfonyl) amino)
-N-hydroxy-3-methyl butyramide
Combine with benzylamine;
1H NMR (DMSO-d
6): δ 10.72 (s, 1H), 8.89 (s, 1H), 8.39 (m, 1H), 7.74 (d, J=9.0Hz, 2H), 7.32-7.21 (m, 5H), 7.05 (d, J=9.0Hz, 2H), 4.21 (d, J=5.9Hz, 2H), 4.02-3.87 (m, 1H), 3.82 (s, 3H), 3.63 (d, J=10.8Hz, 1H), 3.29-3.17 (m, 1H), 2.71-2.57 (m, 1H), 2.52-2.40 (m, 1H), 2.06-1.94 (m, 1H), 0.77 (d, J=6.6Hz, 3H), 0.74 (d, J=6.5Hz, 3H); MS (LSIMS): m/z 464 (M+H); The HRMS theoretical value is: C
22H
30N
3O
6S (M+H): 464.1855, actual recording: 464.1832.
Embodiment 4
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-((pyridine-3-
Ylmethyl) amino ethyl formamyl)))-3-methylbutyryl amine
Combine with 3-pyridyl methylamine:
1H NMR (DMSO-d
6): δ 10.72 (s, 1H), 8.89 (s, 1H), 8.49-8.42 (m, 3H), 7.73 (d, J=8.9Hz, 2H), 7.63-7.60 (m, 1H), 7.32 (dd, J=4.8,7.8Hz, 1H), 7.05 (d, J=8.9Hz, 2H), 4.23 (d, J=5.8Hz, 2H), 4.00-3.88 (m, 1H), 3.81 (s, 3H), 3.62 (d, J=10.8Hz, 1H), 3.27-3.17 (m, 1H), 2.69-2.58 (m, 1H), 2.52-2.41 (m, 1H), 2.07-1.94 (m, 1H), 0.76 (d, J=6.5Hz, 3H), 0.72 (d, J=6.4Hz, 3H); MS (LSIMS): m/z 465 (M+H).
Embodiment 5
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-(picoline-3
-ylmethyl formamyl) amino ethyl))-3-methylbutyryl amine
Combine with 3-(N-methylamino-methyl) pyridine:
1H NMR (DMSO-d
6): δ 10.75 (br s, 1H), 8.92 (s, 1H), 8.52-8.29 (m, 2H), 7.75 (d, J=8.8Hz, 1.4H), 7.67 (d, J=8.8Hz, 0.6H), 7.62-7.58 (m, 1H), 7.42-7.32 (m, 1H), 7.06 (d, J=8.8Hz, 1.4H), 7.01 (d, J=8.8Hz, 0.6H), 4.55-4.41 (m, 2H), 3.94-3.82 (m, 1H), 3.81 (s, 2.1H), 3.80 (s, 0.9H), 3.68-3.60 (m, 1H), 3.33-3.19 (m, 1H), and 2.90-2.50 (m, 2H), 2.88 (s, 2.1H, overlapping), 2.79 (s, 0.9H), 2.05-1.80 (m, 1H), 0.79-0.63 (m, 6H); MS (thermojet): m/z 479 (M+H), 364.
Embodiment 6
4-(3-((1-(R)-1-hydroxyl amino formyl radical-2-methyl-propyl) (4-
The methoxy benzene sulfonyl) piperazine-1-carboxylic acid propionyl amino)), the tert-butyl ester
Combine with the 1-piperazine carboxylic acid tert-butyl ester:
1H NMR (DMSO-d
6): δ 10.77 (br s, 1H), 8.93 (s, 1H), 7.74 (d, J=8.9Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 3.90-3.80 (m, 1H), 3.82 (s, 3H, overlapping), 3.64 (d, J=10.8Hz, 1H), 3.60-3.16 (m, 9H), 2.80-2.71 (m, 1H), 2.59-2.47 (m, 1H), 2.03-1.91 (m, 1H), 1.39 (s, 9H), 0.77 (d, J=6.5Hz, 3H), 0.71 (d, J=6.5Hz, 3H); MS (thermojet): m/z 543 (M+H), 443,382,328.
Embodiment 7
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-oxo-3-piperazine
-1-base propyl group) amino)-3-methylbutyryl amine salt acidulants
With 4-(3-((1-(R)-1-hydroxyl amino formyl radical-2-methyl-propyl) (4-methoxy benzene sulfonyl) amino) propionyl) piperazine-1-carboxylic acid, (430mg, methylene dichloride 0.79mmol) (11mL) solution is cooled to 0 ℃ to the tert-butyl ester (embodiment 6).In this solution, fed hydrogen chloride gas about 0.5 minute then.Be heated to room temperature afterwards and stir more than 1 hour.Volatile matter is removed in evaporation, and resistates filters with washed with dichloromethane, obtains solid 2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (3-oxo-3-piperazine-1-base propyl group) amino)-3-methylbutyryl amine salt acidulants, 375mg (99%).
1H?NMR(DMSO-d
6)：δ10.78(br?s，1H)，9.16(br?s，1H)，7.74(d，J＝8.8Hz，2H)，7.07(d，J＝8.9Hz，2H)，3.82(s，3H)，3.62(br?s，4H)，3.38-3.18(m，1H)，3.16-3.07(br?s，2H)，3.07-2.98(br?s，2H)，2.83-2.73(m，1H)，2.65-2.53(m，1H)，2.06-1.90(m，1H)，0.76(d，J＝6.5Hz，3H)，0.72(d，J＝6.5Hz，3H)。A wide water peak is arranged between δ 4.0-3.5, and it has hidden some signal of this compound; MS (thermojet): m/z 443 (M+H), 382,328.
Embodiment 8
2-(R)-2-((benzyl count off base formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-
N-hydroxy-3-methyl butyramide
To 2-(R)-2-(carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 1) (905mg, 2.08mmol) methylene dichloride (18mL) solution in add triethylamine (0.72ml successively, 5.14mmol), benzylamine (0.25mL, 2.29mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (1.01g, 2.28mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is with 0.5N hydrochloric acid soln and salt water washing, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography obtains 2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate with 2: 5: 16 dichloromethane/ethyl acetate/hexane liquid wash-out, is transparent oily matter, 933mg (86%).
(933mg adds 10% palladium carbon (85mg) in ethanol 1.17mmol) (50mL) solution to 2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate.This mixture stirred 4 hours under the 3 air pressure hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains white foam shape thing 2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid behind the evaporating solvent, 755mg (98%).
To 2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid (655mg; 1.51mmol) and 1-1-Hydroxy Benzotriazole hydrate (224mg; 1.46mmol) anhydrous dimethyl formamide (15mL) solution in add hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (316mg, 1.65mmol).Stir after 30 minutes, the order add oxammonium hydrochloride (416mg, 6.0mmol) and N-methylmorpholine (0.99mL, 9.0mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is water, 0.5N hydrochloric acid soln and salt water washing successively, obtains white foam shape thing with dried over mgso and vacuum concentration.This material silica gel column chromatography obtains 2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide with eluent ethyl acetate, is white foam shape thing, 570mg (84%);
1H NMR (DMSO-d
6): δ 10.75 (br s, 1H), 8.90 (s, 1H), 8.47 (m, 1H), 7.85 (d, J=8.9Hz, 2H), 7.83-7.19 (m, 5H), 7.04 (d, J=8.9Hz, 2H), 4.37 (d, J=11.4Hz, 1H), 4.28 (d, J=5.9Hz, 2H), 3.89 (d, J=11.4Hz, 1H), 3.82 (s, 3H), 3.45 (d, J=10.3Hz, 1H), 1.90-1.79 (m, 1H), 0.73 (d, J=6.3Hz, 6H); MS (LSIMS): m/z 450 (M+H).
Embodiment 9
2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)
-N-hydroxy-3-methyl butyramide
To 2-(R)-2-(carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 1) (1.05g, 2.41mmol) methylene dichloride (20mL) solution in add triethylamine (0.84mL successively, 6.0mmol), N-benzyl methylamine (0.34mL, 2.63mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (1.17g, 2.69mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is with 0.5N hydrochloric acid soln and salt water washing, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography; hexane liquid wash-out (adding a small amount of methylene dichloride so that sample is loaded on the post) with 35% ethyl acetate obtains 2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate; be transparent oily matter, 1.14g (88%).
(1.14g adds 10% palladium carbon (400mg) in ethanol 2.12mmol) (100mL) solution to 2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate.This mixture stirred 3 hours under the 3 air pressure hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains white foam shape thing 2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid behind the evaporating solvent, 902mg (95%).
To 2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid (902mg; 2.01mmol) methylene dichloride (20mL) solution in add triethylamine (0.90ml successively; 6.42mmol), 0-allyl group oxammonium hydrochloride (242mg; 2.21mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (978mg, 2.21mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is with 0.5N hydrochloric acid soln and salt water washing, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography obtains oily matter 2-(R)-N-allyloxy-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3-methylbutyryl amine, 1.008g (100%) with the acetic acid ethyl fluid wash-out of 40% hexane.
To 2-(R)-N-allyloxy-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-3-methylbutyryl amine (500mg; 0.99mmol) methylene dichloride (40mL) solution in add two (triphenylphosphine) Palladous chloride (II) (280mg; 0.4mmol) after; dropwise add again tributyltin hydride (0.43mL, 2.2mmol).After this solution at room temperature stirred 1 hour, with methylene dichloride dilution, the washing of 1N hydrochloric acid soln, dried over mgso also concentrated.Resistates is dissolved in the ethyl acetate after-filtration and removes solid.After concentrating, filtrate is used silica gel column chromatography, and the chloroform solution wash-out with chloroform and 2% methyl alcohol obtains white solid successively: 2-(R)-2-((benzyl methylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide (340mg, 74%).
1H NMR (DMSO-d
6): δ 10.66 (br s, 1H), 8.87 (br s, 0.6H), 8.84 (s, 0.4H), 7.91 (d, J=8.9Hz, 1.2H), 7.78 (d, J=8.9Hz, 0.8H), 7.43-7.21 (m, 5H), 7.05 (d, J=8.9Hz, 1.2H), 7.00 (d, J=8.9Hz, 0.8H), 4.72 (d, J=17.7Hz, 0.4H), 4.70 (d, J=17.7Hz, 0.6H), 4.59-4.42 (m, 1H), 4.25 (d, J=17.8Hz, 0.6H), 4.07 (d, J=17.7Hz, 0.4H), 3.82 (s, 3H), 3.46-3.40 (m, 1H), 2.91 (s, 1.8H), 2.83 (s, 1.2H), 1.92-1.70 (m, 1H), 0.75-0.69 (m, 6H); MS (thermojet): m/z 464 (M+H), 307,239.
With the similar approach of describing among the embodiment 9, so that (carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 1) is an initiator with following amine bonded 2-(R)-2-, the title compound of preparation embodiment 10-11.
Embodiment 10
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl)-((2-morpholine-4-
Base ethylamino formyl radical) amino methyl))-3-methylbutyryl amine
Combine with 4-(2-amino-ethyl) morpholine;
1H NMR (DMSO-d
6): δ 10.74 (br s, 1H), 8.90 (br s, 1H), 7.84 (br s, 1H, overlapping), 7.84 (d, J=8.8Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 4.33 (d, J=17.5Hz, 1H), 3.83 (s, 3H), 3.78 (d, J=17.5Hz, 1H), 3.57-3.54 (m, 4H), 3.49 (d, J=10.2Hz, 1H), 3.28-3.06 (m, 2H), 2.34-2.30 (m, 6H), and 1.93-1.77 (m, 1H), 0.77-0.74 (m, 6H).
Embodiment 11
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-oxo-2-pyrroles
Alkane-1-base ethyl) amino)-3-methylbutyryl amine
Combine with tetramethyleneimine;
1H NMR (CD
3OD): δ 7.90 (d, J=8.9Hz, 2H), 7.04 (d, J=8.9Hz, 2H), 4.50 (d, J=17.6Hz, 1H), 4.15 (d, J=17.6Hz, 1H), 3.87 (s, 3H), 3.56-3.39 (m, 5H), 2.07-1.82 (m, 5H), 0.83 (d, J=6.6Hz, 3H), 0.73 (d, J=6.6Hz, 3H); MS (thermojet): m/z 414 (M+1); The HRMS theoretical value is: C
18H
28N
3O
6S (M+H): 414.1699, actual recording: 414.1703.
Embodiment 12
2-(formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino)-N-hydroxyl-3-
Methylbutyryl amine
With 2-(R)-2-(carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 1) (1.89g, thionyl chloride 4.34mmol) (25mL) vlil 1 hour.The cooling back is steamed and is removed excessive thionyl chloride.Resistates is dissolved in methylene dichloride (50mL) back to be cooled off on ice bath.In this solution, slowly fed dimethylamine gas 1 hour.Behind the evaporating solvent, resistates is dissolved in ethyl acetate, uses 1N hydrochloric acid soln, water and salt water washing, also concentrate with dried over mgso and obtain oily matter: formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino-benzyl 3-methylbutyrate, 1.77g (88%).
(1.77g adds 10% palladium carbon (644mg) in ethanol 3.83mmol) (100mL) solution to formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino-benzyl 3-methylbutyrate.This mixture stirred 1.5 hours under the 3 air pressure hydrogen in the Pa Er wobbler.(aperture 0.45 μ m) removes by filter catalyzer with nylon, obtains white foam shape thing behind the evaporating solvent: formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino-3 Methylbutanoic acid, 1.42mg (100%).
To dimethyl formyl formyl radical methyl (4-methoxy benzene sulfonyl) amino-3 Methylbutanoic acid (1.42g; 3.81mmol) and 1-1-Hydroxy Benzotriazole hydrate (687mg; 4.48mmol) anhydrous dimethyl formamide (7mL) solution in add hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (974mg, 5.0gmmol).Stir after 30 minutes, the order add oxammonium hydrochloride (1.17g, 16.8mmol) and N-methylmorpholine (2.8mL, 25.5mmol).This mixture at room temperature stirs the final vacuum that spends the night and concentrates.Resistates is dissolved in ethyl acetate, gained solution is water, 0.5N hydrochloric acid soln and salt water washing successively, obtain oily matter with dried over mgso and vacuum concentration then, with this material silica gel column chromatography, carry out wash-out with the chloroform solution of the chloroform solution of ethyl acetate, 5% methyl alcohol and 10% methyl alcohol successively and obtain 2-(formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide, be white solid, 390mg (26%);
1H NMR (DMSO-d
6): δ 10.70 (br s, 1H), 8.89 (s, 1H), 7.80 (d, J=8.9Hz, 2H), 7.10 (d, J=8.9Hz, 2H), 4.62 (d, J=17.7Hz, 1H), 4.14 (d, J=17.7Hz, 1H), 3.84 (s, 3H), 3.40 (d, J=10.4Hz, 1H), 2.97 (s, 3H), 2.82 (s, 3H), 1.88-1.72 (m, 1H), 0.72 (d, J=6.5Hz, 6H); MS (thermojet): m/z 388 (M+1); The HRMS theoretical value is: C
16H
26N
3O
6S (M+H): 388.1542, actual recording: 388.1592.
Embodiment 13
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (((pyridin-3-yl first
Base) amino methyl formamyl)))-3-methylbutyryl amine
Similar approach with embodiment 12; (carboxymethyl (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 1) is an initiator with 2-(R)-2-; and it is combined with the 3-pyridyl-methanamine, thereby make 2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (((pyridin-3-yl methyl) formamyl) methyl) amino)-3-methylbutyryl amine through chloride of acid.
1H NMR (CD
3OD): δ 8.55-8.53 (m, 1H), 8.43-8.40 (m, 1H), 7.90-7.82 (m, 1H, overlapping), 7.86 (d, J=8.9Hz, 2H), 7.40 (dd, J=4.8,7.8Hz, 1H), 7.04 (d, J=8.9Hz, 2H), 4.50 (d, J=17.5Hz, 1H), 4.39 (d, J=17.5Hz, 1H), 4.32 (d, J=17.7Hz, 1H), 4.02 (d, J=17.7Hz, 1H), 3.87 (s, 3H), 3.60 (d, J=10.3Hz, 1H), 2.08-1.93 (m, 1H), 0.85 (d, J=6.5Hz, 3H), 0.70 (d, J=6.5Hz, 3H); MS (thermojet): m/z 451 (M+H), 336,320.
Embodiment 14
N-hydroxyl-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) ammonia
Base) ethanamide
To acetimidic acid disodium salt monohydrate (5.0g, 25.6mmol) in De diox (50mL) and water (50mL) solution order add triethylamine (5.3ml, 38mmol) and 4-methoxy benzene sulfonyl chloride (5.8g, 28.0mmol).This mixture at room temperature stirs the back of spending the night and dilutes with methylene dichloride.This solution 1N hydrochloric acid soln, water and salt water washing, dried over mgso, vacuum concentration obtains (carboxymethyl (4-methoxy benzene sulfonyl) amino) acetate, is white solid, 3.83g (49%).
Making carboxymethyl (4-methoxy benzene sulfonyl) amino by mild heat) (0.5g 1.65mmol) is dissolved in anhydrous acetic acid (15mL) to acetate.Gained solution at room temperature stirs and spends the night.Vacuum is steamed and is removed anhydrous acetic acid; Resistates is dissolved in methylene dichloride and add morpholine (0.16mL, 1.82mmol).This mixture at room temperature stirs and spends the night, then vacuum concentration.After resistates is dissolved in ethyl acetate, with 1N hydrochloric acid soln, water and salt water washing, dried over mgso and concentrated oily matter ((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino) acetate, the 0.33g (54%) of obtaining.
To ((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino) acetate (0.33g, 0.89mmol) methylene dichloride (10mL) solution in add triethylamine (0.43ml successively, 3.1mmol), 0-benzyl oxammonium hydrochloride (0.15g, 0.94mmol) and phosphofluoric acid (benzotriazole-1-base oxygen) three (dimethylamino) phosphorus father-in-law (0.43g, 0.97mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.This solution is used 0.5N hydrochloric acid soln, water and salt water washing successively, with dried over mgso and vacuum concentration.The resistates silica gel column chromatography obtains N-benzyloxy-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino) ethanamide with eluent ethyl acetate, is white solid, 0.33g (78%).
(0.33g adds 5% palladium carbon (85mg) in methyl alcohol 0.69mmol) (35mL) solution to N-benzyloxy-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino) ethanamide.This mixture stirred 1.5 hours under the 2 air pressure hydrogen in the Pa Er wobbler.Remove by filter evaporating solvent behind the catalyzer with nylon (aperture 0.45 μ m).The resistates silica gel column chromatography obtains N-methoxyl group-((4-methoxy benzene sulfonyl) (2-morpholine-4-base-2-oxoethyl) amino) ethanamide with the dichloromethane solution wash-out of 5% methyl alcohol, is white solid, 65mg (24%);
1H NMR (CD
3OD): δ 7.82 (d, J=9.0Hz, 2H), 7.08 (d, J=9.0Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.58-3.50 (m, 4H); MS (thermojet): m/z 388 (M+1), 387 (M); The HRMS theoretical value is: C
16H
22N
3O
7S (M+H): 388.1178, actual recording: 338.1180.
According to the similar approach of describing among the embodiment 14, be initiator with (carboxymethyl (4-methoxy benzene sulfonyl) amino) acetate, after with anhydrous acetic acid it being handled, it is combined with following amine, thereby make the title compound of embodiment 15-16.
Embodiment 15
N-hydroxyl-((4-methoxy benzene sulfonyl) (2-oxo-2-tetramethyleneimine-1-base ethyl)
Amino) ethanamide
Combine with tetramethyleneimine;
1H NMR (DMSO-d
6): δ 11.26 (brs, 1H), 8.89 (s, 1H), 7.81 (d, J=8.9Hz, 2H), 7.10 (d, J=8.9Hz, 2H), 4.09 (s, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.45-3.25 (m, 4H), 1.93-1.72 (m, 4H); MS (thermojet): m/z 372 (M+1): the ultimate analysis theoretical value is C
15H
21N
3O
6S:C, 48.51; H, 5.70; N, 11.31.Actual recording: C, 48.51; H, 5.82; N, 11.24.
Embodiment 16
2-(formyl-dimethylamino methyl (4-methoxy benzene sulfonyl) amino)-N-hydroxyl acetamide
Combine with dimethylamine; Mp:170 ℃.(dec.);
1H NMR (DMSO-d
6): δ 10.69 (br s, 1H), 8.88 (s, 1H), 7.91 (d, J=8.9Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 4.19 (s, 2H), 3.85 (s, 3H), 3.73 (s, 2H), 2.94 (s, 3H), 2.84 (s, 3H); MS (thermojet): m/z 346 (M+1): the ultimate analysis theoretical value is C
13H
19N
3O
6S:C, 45.21; H, 5.55; N, 12.17.Actual recording: C, 44.93; H, 5.61; N, 12.03.
Embodiment 17
2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-
N-hydroxy-3-methyl butyramide
To 2-(R)-2-((2-propyloic (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate (embodiment 2) (and 900mg, add in methylene dichloride 2.0mmol) (10mL) solution thionyl chloride (0.16mL, 2.2mmol).This reaction mixture at room temperature stirs 1.5 hours final vacuums and concentrates.After resistates is dissolved in methylene dichloride (10mL), in this solution, fed ammonia 0.5 minute.This solution at room temperature stirs the vacuum concentration then that spends the night.Resistates carries out flash chromatography with silica gel, obtains 2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl benzyl butyrate with the chloroform solution wash-out of 2% methyl alcohol, is transparent oily matter (275mg, 31%).
(add 10% palladium carbon (30mg) among the 275mg, ethanolic soln 0.61mmol) (15mL) to 2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl benzyl butyrate.This mixture stirred 5 hours under the 3 air pressure hydrogen in the Pa Er wobbler.Evaporating solvent obtains white foam shape thing: 2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyric acid, 211mg (96%) after removing catalyzer with diatomite filtration.
To 2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyric acid (205mg; 0.57mmol) and 1-1-Hydroxy Benzotriazole hydrate (85mg; 0.55mmol) anhydrous dimethyl formamide (5mL) solution in add hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (120mg, 0.63mmol).Stir after 30 minutes, the order add oxammonium hydrochloride (158mg, 2.3mmol) and N-methylmorpholine (0.37mL, 3.4mmol).This mixture at room temperature stirs the back of spending the night and dilutes with ethyl acetate.Gained solution with water and salt water washing, obtain oily matter with dried over mgso and vacuum concentration then, with this material silica gel column chromatography, chloroform solution wash-out with 2% methyl alcohol obtains 2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide, be white solid, 45mg (21%);
1H NMR (DMSO-d
6): δ 10.74 (br s, 1H), 8.91 (br s, 1H), 7.74 (d, J=8.8Hz, 2H), 7.33 (br s, 1H), 7.07 (d, J=8.8Hz, 2H), 6.79 (brs, 1H), 3.93-3.82 (m, 1H, overlapping), 3.83 (s, 3H), 3.64 (d, J=10.7Hz, 1H), 3.25-3.12 (m, 1H), 2.62-2.48 (m, 1H), 2.42-2.30 (m, 1H), 2.06-1.94 (m, 1H), 0.79 (d, J=6.6Hz, 3H), 0.76 (d, J=6.6Hz, 3H); MS (thermojet): m/z374 (M+H).
Embodiment 18
2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl)-amino)-
N-hydroxy-3-methyl butyramide
Under 80 ℃, with N, (1.9mL, toluene 7.9mmol) (15mL) drips of solution is added to 2-(R)-2-, and ((2-propyloic) (4-methoxy benzene sulfonyl) amino)-(900mg is in toluene solution 2.0mmol) for benzyl 3-methylbutyrate (embodiment 2) for dinethylformamide di-t-butyl acetal.80 ℃ the heating 2 hours after, with this mixture cooling and the concentrated amber oil that obtains, this oil silica gel column chromatography obtains oily matter with the chloroform wash-out: 2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate, 3.75mg (37%).
(370mg adds 10% palladium carbon (40mg) in ethanol 0.73mmol) (20mL) solution to 2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-benzyl 3-methylbutyrate.This mixture stirred 5 hours under the 3 air pressure hydrogen in the Pa Er wobbler.Evaporating solvent obtains white foam shape thing: 2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid, 30mg (100%) after removing catalyzer with diatomite filtration.
To 2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-3 Methylbutanoic acid (303mg, 0.73mmol) and 1-1-Hydroxy Benzotriazole hydrate (108mg, 0.70mmol) anhydrous dimethyl formamide (10mL) solution in add hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (153mg, 0.80mmol).Stir after 45 minutes, the order add oxammonium hydrochloride (203mg, 2.9mmol) and N-methylmorpholine (0.48mL, 4.4mmol).This mixture at room temperature stirs the final vacuum that spends the night and concentrates.The resistates silica gel column chromatography, behind the chloroform solution wash-out with 2% methyl alcohol, hexane liquid wash-out with 10% ethyl acetate obtains 2-(R)-2-((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide again, is white foam shape thing, 135mg (43%);
1H NMR (DMSO-d
6): δ 10.77 (br s, 1H), 7.74 (d, J=8.9Hz, 2H), 7.08 (d, J=8.9Hz, 2H), 3.93-3.82 (m, 1H, overlapping), 3.83 (s, 3H), 3.64 (d, J=10.8Hz, 1H), 3.26-3.14 (m, 1H), and 2.70-2.60 (m, 1H), 2.50-2.38 (m, 1H), 2.04-1.91 (m, 1H), 1.38 (s, 9H), 0.78 (d, J=6.5Hz, 3H), 0.72 (d, J=6.5Hz, 3H); MS (thermojet): m/z 431 (M+H), 375,314.
Embodiment 19
2-(R)-2-((2-propyloic) (4-methoxy benzene sulfonyl) amino)-N-hydroxyl
-3-methylbutyryl amine
At 0 ℃, ((2-tertiary butyloxycarbonyl ethyl) (4-methoxy benzene sulfonyl) amino)-(100mg adds trifluoroacetic acid (1mL) in methylene dichloride 0.23mmol) (1mL) solution to N-hydroxy-3-methyl butyramide (embodiment 18) to 2-(R)-2-.This mixture heating up to room temperature and stirring spent the night.After the evaporation of trifluoroacetic acid and methylene dichloride, resistates is through silica gel column chromatography, carries out wash-out with the chloroform solution of 5% methyl alcohol.Obtain 2-(R)-2-(2-propyloic (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide after suitable cut concentrated, be white solid, 35mg (41%).
1H NMR (DMSO-d
6): δ 10.79 (brs, 1H), 8.97 (br s, 1H), 7.76 (d, J=8.9Hz, 2H), 7.09 (d, J=8.9Hz, 2H), 3.95-3.82 (m, 1H, overlapping), 3.84 (s, 3H), 3.66 (d, J=10.8Hz, 1H), and 3.30-3.20 (m, 1H), 2.73-2.62 (m, 1H), 2.50-2.40 (m, 1H), 2.07-1.94 (m, 1H), 0.80 (d, J=6.5Hz, 3H), 0.74 (d, J=6.5Hz, 3H); MS (thermojet): m/z 375 (M+H), 314.
Claims (12)
1. formula I compound or its pharmacy acceptable salt
Wherein:
N is 1-6;
X is hydroxyl, (C
1-C
6) alkoxyl group or NR
1R
2, R wherein
1And R
2Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
5(C
2-C
6) alkyl, (C
1-C
5) alkyl (CHR
5) (C
1-C
6) alkyl, wherein R
5Be hydroxyl, (C
1-C
6) acyloxy, (C
1-C
6) alkoxyl group, (C
1-C
6) acyl amino, (C
1-C
6) alkyl sulfenyl, (C
6-C
10) arylthio, (C
1-C
6) alkyl sulfinyl, (C
6-C
10) aryl sulfinyl, (C
1-C
6) alkylsulfonyloxy, (C
6-C
10) aryl-sulfonyl oxygen, amino, (C
1-C
6) alkylamino, ((C
1-C
6) alkyl)
2Amino; And CH (R
7) COR
8, R wherein
7Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
1-C
6) alkylthio (C
1-C
6) alkyl, (C
6-C
10) aryl sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkyl sulfinyl (C
1-C
6) alkyl, (C
6-C
10) aryl sulfinyl (C
1-C
6) alkyl, (C
1-C
6) alkyl sulfonyl (C
1-C
6) alkyl, (C
6-C
10) arylsulfonyl (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, (C
1-C
6) alkylamino (C
1-C
6) alkyl, ((C
1-C
6) alkylamino)
2(C
1-C
6) alkyl, R
9R
10NCO (C
1-C
6) alkyl or R
9OCO (C
1-C
6) alkyl, wherein R
9And R
10Be independently of one another: hydrogen, (C
1-C
6) alkyl and (C
6-C
10) aryl (C
1-C
6) alkyl; R
8Be R
11O or R
11R
12N, wherein R
11And R
12Be independently of one another: hydrogen, (C
1-C
6) alkyl and (C
6-C
10) aryl (C
1-C
6) alkyl;
R
3And R
4Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, trifluoromethyl, trifluoromethyl (C
1-C
6) alkyl, (C
1-C
6) alkyl (difluoro methylene), (C
1-C
3) alkyl (difluoro methylene) (C
1-C
3) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) amido (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) amido (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) alkylthio (C
1-C
6) alkyl, (C
6-C
10) aryl sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkyl sulfinyl (C
1-C
6) alkyl, (C
6-C
10) aryl sulfinyl (C
1-C
6) alkyl, (C
1-C
6) alkyl sulfonyl (C
1-C
6) alkyl, (C
6-C
10) arylsulfonyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, (C
1-C
6) alkylamino (C
1-C
6) alkyl, ((C
1-C
6) alkylamino)
2(C
1-C
6) alkyl, R
13CO (C
1-C
6) alkyl, wherein R
13Be R
20O or R
20R
21N, R
20Or R
21Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, or (C
6-C
10) aryl (C
1-C
6) alkyl;
Perhaps R
3And R
4, perhaps R
20And R
21Form together: (C
3-C
6) cycloalkyl, the oxa-cyclohexyl, the sulfo-cyclohexyl, 2,3-indanyl or 1,2,3,4-tetralin basic ring and
Ar is (C
6-C
10) aryl, (C
1-C
6) alkyl (C
6-C
10) aryl, (C
1-C
6) alkoxyl group (C
6-C
10) aryl, ((C
1-C
6) alkoxyl group)
2(C
6-C
10) aryl, (C
6-C
10) aryloxy (C
6-C
10) aryl,
But condition is to work as R
1Or R
2One of be CH (R
7) COR
8, R wherein
7And R
8When defining as above, another R
1Or R
2Be hydrogen, (C
1-C
6) alkyl, or benzyl.
2. according to the compound of claim 1, wherein n is 2.
3. according to the compound of claim 1, wherein Ar is 4-methoxyphenyl or 4-phenoxy phenyl.
4. according to the compound of claim 1,2 or 3, R wherein
3Or R
4One of be not hydrogen.
5. according to the compound of claim 1, wherein n is 1, and R
1Or R
2One of be hydrogen.
6. according to the compound of claim 4, wherein X is a hydrogen, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl.
7. according to the compound of claim 4, wherein X is an alkoxyl group, and Ar is 4-methoxyphenyl or 4-phenoxy phenyl.
8. according to the compound of claim 1, wherein Ar is 4-methoxyphenyl or 4-phenoxy phenyl, and R
3And R
4Constitute (C together
3-C
6) cycloalkyl group, the amylene oxide base, the sulfo-cyclohexyl, or 2, the 3-indanyl.
9. according to the compound of claim 1, wherein said compound is selected from:
2-(R)-2-((2-benzylamino formyl radical ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R)-2-((benzylamino formyl radical methyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R)-2-((2-propyloic) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
((2-propyloic) (3,4-dimethoxy-benzene sulphonyl) amino)-N-hydroxyl-ethanamide;
2-(R)-2-((2-formamyl ethyl) (4-methoxy benzene sulfonyl) amino)-N-hydroxy-3-methyl butyramide;
2-(R)-N-hydroxyl-2-((4-methoxy benzene sulfonyl) (2-(methyl carboxymethylamino formyl radical) ethyl) amino)-3-methylbutyryl amine.
10. pharmaceutical composition, this pharmaceutical composition is made up of claim 1 compound of significant quantity or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
11. claim 1 compound or its pharmacy acceptable salt be (a) matrix metalloproteinase in preparation suppresses to comprise people's mammalian body, or (b) purposes in the medicine that produces of tumour necrosis factor.
12. the preparation method of formula I compound or its pharmacy acceptable salt
Wherein:
N is 1-6;
X is hydroxyl, (C
1-C
6) alkoxyl group or NR
1R
2, R wherein
1And R
2Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, R
5(C
2-C
6) alkyl, (C
1-C
5) alkyl (CHR
5) (C
1-C
6) alkyl, wherein R
5Be hydroxyl, (C
1-C
6) acyloxy, (C
1-C
6) alkoxyl group, (C
1-C
6) acyl amino, (C
1-C
6) alkyl sulfenyl, (C
6-C
10) arylthio, (C
1-C
6) alkyl sulfinyl, (C
6-C
10) aryl sulfinyl, (C
1-C
6) alkylsulfonyloxy, (C
6-C
10) aryl-sulfonyl oxygen, amino, (C
1-C
6) alkylamino, ((C
1-C
6) alkyl)
2Amino; And CH (R
7) COR
8, R wherein
7Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
1-C
6) alkylthio (C
1-C
6) alkyl, (C
6-C
10) aryl sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkyl sulfinyl (C
1-C
6) alkyl, (C
6-C
10) aryl sulfinyl (C
1-C
6) alkyl, (C
1-C
6) alkyl sulfonyl (C
1-C
6) alkyl, (C
6-C
10) arylsulfonyl (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, (C
1-C
6) alkylamino (C
1-C
6) alkyl, ((C
1-C
6) alkylamino)
2(C
1-C
6) alkyl, R
9R
10NCO (C
1-C
6) alkyl or R
9OCO (C
1-C
6) alkyl, wherein R
9And R
10Be independently of one another: hydrogen, (C
1-C
6) alkyl and (C
6-C
10) aryl (C
1-C
6) alkyl; R
8Be R
11O or R
11R
12N, wherein R
11And R
12Be independently of one another: hydrogen, (C
1-C
6) alkyl and (C
6-C
10) aryl (C
1-C
6) alkyl;
R
3And R
4Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, trifluoromethyl, trifluoromethyl (C
1-C
6) alkyl, (C
1-C
6) alkyl (difluoro methylene), (C
1-C
3) alkyl (difluoro methylene) (C
1-C
3) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
6-C
10) aryl, (C
6-C
10) aryl (C
6-C
10) aryl (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) amido (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) amido (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) alkylthio (C
1-C
6) alkyl, (C
6-C
10) aryl sulfo-(C
1-C
6) alkyl, (C
1-C
6) alkyl sulfinyl (C
1-C
6) alkyl, (C
6-C
10) aryl sulfinyl (C
1-C
6) alkyl, (C
1-C
6) alkyl sulfonyl (C
1-C
6) alkyl, (C
6-C
10) arylsulfonyl (C
1-C
6) alkyl, amino (C
1-C
6) alkyl, (C
1-C
6) alkylamino (C
1-C
6) alkyl, ((C
1-C
6) alkylamino)
2(C
1-C
6) alkyl, R
13CO (C
1-C
6) alkyl, wherein R
13Be R
20O or R
20R
21N, R
20Or R
21Be following radicals independently of one another: hydrogen, (C
1-C
6) alkyl, or (C
6-C
10) aryl (C
1-C
6) alkyl;
Perhaps R
3And R
4, perhaps R
20And R
21Form together: (C
3-C
6) cycloalkyl, oxa-cyclohexyl, sulfo-cyclohexyl, 2,3-indanyl or 1,2,3,4-tetralin basic ring; With
Ar is (C
6-C
10) aryl, (C
1-C
6) alkyl (C
6-C
10) aryl, (C
1-C
6) alkoxyl group (C
6-C
10) aryl, ((C
1-C
6) alkoxyl group)
2(C
6-C
10) aryl, (C
6-C
10) aryloxy (C
6-C
10) aryl;
But condition is to work as R
1Or R
2One of be CH (R
7) COR
8, R wherein
7And R
8When defining as above, another R
1Or R
2Be hydrogen, (C
1-C
6) alkyl, or benzyl; Comprise allowing compound as follows and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-1-Hydroxy Benzotriazole and azanol react:
Wherein n, X, R
3, R
4With Ar as defined above.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40104995A | 1995-03-08 | 1995-03-08 | |
| US08/401,049 | 1995-03-08 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01111743A Division CN1316419A (en) | 1995-03-08 | 2001-03-23 | Arenesulfonyl amino-iso hydroximic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1181066A CN1181066A (en) | 1998-05-06 |
| CN1122662C true CN1122662C (en) | 2003-10-01 |
Family
ID=23586059
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96193213A Expired - Fee Related CN1122662C (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| CN01111743A Pending CN1316419A (en) | 1995-03-08 | 2001-03-23 | Arenesulfonyl amino-iso hydroximic acid derivative |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01111743A Pending CN1316419A (en) | 1995-03-08 | 2001-03-23 | Arenesulfonyl amino-iso hydroximic acid derivative |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US5863949A (en) |
| EP (1) | EP0813520B1 (en) |
| JP (1) | JP3753737B2 (en) |
| KR (1) | KR100269046B1 (en) |
| CN (2) | CN1122662C (en) |
| AR (1) | AR003935A1 (en) |
| AT (1) | ATE211131T1 (en) |
| AU (1) | AU707510B2 (en) |
| BR (1) | BR9607362A (en) |
| CA (1) | CA2214720C (en) |
| CO (1) | CO4700432A1 (en) |
| CZ (1) | CZ291106B6 (en) |
| DE (1) | DE69618179T2 (en) |
| DK (1) | DK0813520T3 (en) |
| ES (1) | ES2169794T3 (en) |
| FI (1) | FI973613A (en) |
| HK (1) | HK1041254A1 (en) |
| HU (1) | HUP9800462A3 (en) |
| IL (1) | IL117343A (en) |
| MX (1) | MX9706850A (en) |
| MY (1) | MY113586A (en) |
| NO (1) | NO313752B1 (en) |
| NZ (1) | NZ303860A (en) |
| PE (1) | PE28797A1 (en) |
| PL (1) | PL184158B1 (en) |
| PT (1) | PT813520E (en) |
| RU (1) | RU2145597C1 (en) |
| TR (1) | TR199700913T1 (en) |
| TW (1) | TW346488B (en) |
| WO (1) | WO1996027583A1 (en) |
| ZA (1) | ZA961876B (en) |
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